Our perception is shaped by our behavioral state. When we are tired we fail to notice normally salient stimuli, when focused on one thing we ignore others, and with practice we can even improve our ability to perceive. While these are basic aspects of experience, the mechanisms in the brain of such 'state dependence' are poorly understood, particularly at the level of neurons and synapses. The convergence of perception and behavioral state is perhaps no more relevant than in primary sensory cortex, where sensory perception and cortical processing first meet. Therefore, it is the goal of this proposal to understand the mechanisms of the state dependence of brain activity in primary sensory cortex. This project uses the auditory system of mice as a model, because hearing is an important, well developed sense for both mice and humans, and because of the relevance for the understanding and potential treatment of deafness, other communication disorders, and psychiatric or neurologic disorders. To 'zoom in' to the cellular and synaptic level in a perceiving and behaving animal this study uses a powerful set of cutting edge techniques: two-photon targeted and blind patch- clamp recording along with custom-developed behavioral and sensory stimulus delivery methods. This integrative approach will hopefully allow us to answer a basic important question about the state dependence of perception. How do the circuit dynamics in auditory cortex change when an animal is alert or mobile when compared to passively sitting still? In particular, we will determine how principal neuron firing is regulated by inhibitory and excitatory synaptic activity, and what types of inhibitory neurons appears to be responsible for the inhibitory component. To do so, we will monitor the movements of the animal on a custom designed treadmill apparatus, and measure alertness by recording the local field potential (LFP) and multiunit firing in multiple forebrain areas. These experiments will provide new insights into the dynamics of cortical sensory responses as they relate to the state of the animal. This work will also provide a foundation of methods and results for future study of how the modulation of perception by behavioral state is perturbed in deafness and brain diseases. PUBLIC HEALTH RELEVANCE: The popular phrase 'mind over matter' expresses the fact that our perception is shaped by our internal state of being, such as: sleepy or alert, or pathological states like hallucinating or depressed. Such 'state dependence' is a complex yet very important facet of our experience and therefore elucidating its brain manifestations has broad implications for understanding the healthy brain and psychiatric illness. This research proposes to explore how the basic cellular and synaptic physiology in auditory cortex, measured in responses to sounds, is altered in mice between different states of wakefulness and locomotion.